It is well known that NK cells can kill tumor cells in vitro and in vivo. It is also known that NK cells can be prevented from killing tumor cells by the interaction of MHC class I molecules and inhibitory receptors on NK cells. Our hypothesis is that the early NK cell-tumor cell interaction is important in determining whether NK cells promote anti-tumor immunity or prevent anti-tumor immunity. These interactions are likely to be important early in the growth phase of a tumor. Furthermore, it may be possible that tumor cells can prevent NK cell effector mechanisms and thus prevent anti-tumor immune responses and promote tumor survival. Data suggest that NK cells are a part of the innate defense against infectious diseases and tumors, and NK cells can influence downstream immunity. The aim of this research proposal is to investigate the extent to which NK cells can alter host responses to tumors and the mechanisms that NK cells employ to activate host macrophages and cytolytic T cells against tumor cells. We hypothesize that NK cell activation is important for the proper activation of macrophages and the production of long-term cytolytic T cells against tumor cells. Our specific aims are: 1) to determine the extent to which NK cell inhibitory receptors prevent the generation of a host anti-tumor response. We will use anti-receptor antibodies and receptor transgenic mice to determine the influence of these inhibitory receptors on anti-tumor immunity. 2) To determine the role of NK cell effector mechanisms in the generation of different macrophage effector functions, so called M1 and M2 macrophages. We will utilize in vitro and in vivo systems with genetically altered mice to test key effector molecules and pathways. 3) To determine the extent to which NK cells can be induced to activate local host anti-tumor immune responses. We will attempt to alter local NK cell activation with tumor specific antibodies and induce inflammatory macrophages. These experiments will involve two murine lymphoma models: RMA andBW-Sp3 tumor cells. We aim to understand how NK-tumor cell interactions promote or fail to promote effective anti-tumor immune responses. These data will have implications for immunotherapy and tumor vaccines and suggest ways to develop more potent tumor immunity. [unreadable] [unreadable]